National Institute of Allergy and Infectious Diseases - August 1991

NIAID's Research Strategy

NIAID's AIDS vaccine program includes basic and clinical research conducted at the National Institutes of Health in Bethesda, Maryland, in 13 multi-institutional National Cooperative Vaccine Development Groups for AIDS (NCVDGs), and at 5 AIDS Vaccine Evaluation Units located at university medical centers nationwide, as well as smaller research efforts. NIAID also supports eight AIDS Cooperative Adjuvant Groups, which have identified several promising candidate adjuvants, substances that boost the immune response to vaccines.

Employing a practical research strategy that balances scientific and public health priorities, NIAID's AIDS vaccine program supports basic research to better understand the immune response to HIV while simultaneously expediting animal model and clinical studies. More pilot studies in humans are needed to provide information critical to assigning priorities to the AIDS vaccine candidates being considered for large-scale efficacy trials. Before efficacy trials can be done, investigators must address some potential problems. One of these is the wide genetic variation found in strains of HIV from one patient to another and even within the same individual over the course of the disease. Many researchers believe a "cocktail" vaccine containing several proteins of the AIDS virus may be the most effective for provoking a broad, strong immune response. Other problems include a host of ethical, legal, and logistical issues. NIAID is working with researchers, public health officials, and others in the United States and abroad to help resolve these issues.

NIAID is planning to support efficacy studies by establishing cooperative agreements with academic research institutions in the United States and other countries. Researchers participating in these NIAID-funded international collaborations would determine the incidence of HIV infection in given populations and conduct pilot vaccine trials.

Research Advances

While the challenges remain daunting, several significant research advances have fueled optimism that the creation of an AIDS vaccine is feasible. Scientists from four NCVDGs have independently demonstrated that a whole virus vaccine can protect monkeys from infection with simian immunodeficiency virus (SIV), a virus similar to HIV. These studies should allow researchers to define more precisely the nature and elements responsible for the protective immunity achieved. Similar results have been reported in at least two chimpanzee studies. Research findings also suggest that a vaccine based on one strain of SIV can protect monkeys against another SIV strain. This work provides hope that variation in the virus may not be as significant an obstacle to vaccine development as had been anticipated.

Other heartening research news includes advances in understanding immune responses to HIV, identification of parts of the virus that may be important to protection, and progress in the clinical evaluation of candidate human AIDS vaccines.

The Immune Response to HIV

One of the biggest obstacles facing AIDS vaccine researchers is the elusive nature of HIV. After infecting a cell, the virus incorporates its genetic material into that of the cell. There the virus can hide indefinitely before some signal prompts the cell to make new viruses. Other cells can act as HIV reservoirs, harboring intact viruses that cannot be detected and destroyed by the immune system.

Unlike most viruses, HIV can be transmitted as either free virus or in infected cells. The latter can spread infection by cell-to-cell contact. The immune system usually mounts a defense against free virus by production antibodies, custom-made proteins that attach to the virus and render it harmless. The immune system can also respond to infection through the direct action of immune cells against virus-infected cells, a response known as cell-mediated immunity. Scientists believe that both types of immune responses are probably necessary to protect against infection with HIV.

Investigators have observed that individuals exposed to HIV may mount cell-mediated immune responses against HIV before they develop HIV antibodies. This has led to an innovative vaccine strategy being tested in NIAID's AIDS Vaccine Evaluation Units. Investigators are using one vaccine that works best to stimulate cell-mediated immunity followed by a different vaccine given as a booster to maximize antibody production.

Mucosal Immunity

Sexual transmission of HIV occurs across mucous membranes that

line the genital tract. An important unanswered question in AIDS vaccine research is what role does mucosal immunity play in the early defense against HIV infection? As yet, no vaccine candidate has protected against mucosal challenge in animals. NIAID-supported scientists have developed substances, however, that can help them study immune responses at mucosal surfaces. They have also taken viruses and bacteria that normally infect mucous membranes and turned them into harmless shuttles that can HIV proteins to mucous membranes and induce these responses. Research in this area may help scientists develop strategies to prevent sexual transmission of HIV.

Recombinant Vaccines

Important immunological targets on HIV and on infected cells have been identified. For example, studies of gp160, the envelope protein of HIV, have shown that it attaches the virus to the cell and also facilitates the fusion of the cell and virus during the early stages of infection. Researchers have found that a recombinant vaccine based on gp 120, a component of gp160, can protect chimpanzees from infection with HIV. Several candidate vaccines based on the envelope protein of the virus are currently being studied in humans.

Recombinant vaccine preparations based on parts of the AIDS virus, called subunit vaccines, are but one vaccine approach being investigated by NIAID-supported researchers. Other strategies include: 0 killed or inactivated whole virus. 0 chemically synthesized peptides (portions of HIV proteins). 0 recombinant live viruses containing HIV genes. 0 anti-idiotypes (antibodies generated against antibodies to the virus).

Currently, five of the six experimental AIDS vaccines being tested in humans by scientists at the NIH Clinical Center and by investigators at the NIAID-support AIDS Vaccine Evaluation Units are recombinant sub-unit vaccines. These studies are evaluating the safety of the vaccines, determining whether the vaccines induce strong immune responses, and comparing responses to different doses of each vaccine.

Three of the candidate vaccines in clinical trials are based on the envelope protein gp160. The first vaccine to be approved for human testing in 1987 was a recombinant form of gp160 produced by genetic engineering technology in insect cells. Ongoing studies have shown that this vaccine produces dose-related antibody responses and induces some cell-mediated immune response.

Another gp160 vaccine being tested in human is a recombinant form with a three-dimensional shape that matches that of the gp160 protein made by native HIV. Experience with other virus vaccines indicates that this match may be important for stimulating a strong immune response.

A third recombinant gp160 vaccine under investigation is made by inserting the genes for the component proteins of gp160 into live vaccinia virus, the virus used in the smallpox vaccine. A live recombinant vaccine offers the advantage of eliciting a stronger immune response than an inactivated vaccine because, as the vaccinia virus multiplies, it produces significant quantities of HIV antigens, proteins that stimulate the immune response.

Currently, five of the six experimental AIDS vaccines being tested in humans by scientists at the NIH Clinical Center and by investigators at the NIAID-supported AIDS Vaccine Evaluation Units are recombinant sub-unit vaccines. These studies are evaluating the safety of the vaccines, determining whether the vaccines induce strong immune responses, and comparing responses to different doses of each vaccine.

Three of the candidate vaccines in clinical trials are based on the envelope protein gp160. The first vaccine to be approved for human testing in 1987 was a recombinant form of gp160 produced by genetic engineering technology in insect cells. Ongoing studies have shown that this vaccine produces dose-related antibody responses and induces some cell-mediated immune response.

Another gp160 vaccine being tested in humans is a recombinant form with a three-dimensional shape that matches that of the gp160 protein made by native HIV. Experience with other virus vaccines indicates that this match may be important for stimulating a strong immune response.

A third recombinant gp160 vaccine under investigation is made by inserting the genes for the component proteins of gp160 into live vaccinia virus, the virus used in the smallpox vaccine. A live recombinant vaccine offers the advantage of eliciting a stronger immune response than an inactivated vaccine because, as the vaccinia virus multiplies, it produces significant quantities of HIV antigens, proteins that stimulate the immune responses.

Two of the experimental vaccines being tested in humans are based on the gp120 component of the envelope protein gp160. The first gp120 vaccine to be studied by the vaccine units is Env-2-3, which is produced in genetically engineered yeast and is being given together with an experimental adjuvant to boost the immune response. In baboons and chimpanzees, this combination elicited strong, consistent antibody and cell-mediated immune responses. A second recombinant gp120 vaccine is made by a different process and is produced in mammalian cells. This gp120 vaccine has been shown to protect chimpanzees from infection with HIV.

Vaccines as Immunotherapy

While the ultimate goal of an effective AIDS vaccine is to prevent infection with HIV, researchers are also examining the use of vaccines as immunotherapy to moderate the course of disease. Vaccines based on the HIV envelope protein, gp160 , and on the HIV core protein, p24, are being studied in asymptomatic HIV-infected individuals to see if the vaccine can stall the progression of HIV disease and delay the onset of symptoms. These studies are being conducted by scientists in NIAID's AIDS Clinical Trails Group, a nationwide network of medical research centers, and in the NIAID intramural program at the NIH Clinical Center.

In a relatively short period of time, tremendous progress has been made toward the development of safe and effective vaccines against HIV and AIDS. Although no clear vaccine candidate for large-scale efficacy trials has yet emerged, scientists predict that such trials will begin within the next few years. The novel techniques and approaches being developed in the race to outwit HIV are extending the frontiers of vaccine research and will benefit not only people at risk for HIV but all those at risk for other intractable infectious diseases.

Published 1991 - National Institute of Allergy and Infectious Diseases . All material contained in this report is in the public domain and may be used and reprinted without special permission; citation to source, however, is appreciated.

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